Endoscopic Management Options for Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) is a prevalent condition that affects a significant portion of the Western population. Despite its benign pathophysiology, it has the potential to cause serious complications over time, ranging from conditions that are benign, premalignant, and/or malignant. Traditional treatment options include lifestyle measures, anti-secretory medications (e.g., proton pump inhibitor (PPI)), and surgical options (e.g., Nissen and Toupet fundoplication). However, recent studies have revealed long-term side effects of anti-secretory medications. Moreover, surgical options, though effective, are considered invasive and associated with potential complications. In the current age of ongoing research in minimally invasive options, endoscopic treatment of GERD has become popular. As a result, procedures such as radiofrequency treatment and transoral incisionless fundoplication (TIF) have gained FDA approval and are currently being covered by most insurance. In this review article, we will discuss pre-procedural workup, appropriate patient selection, advantages, disadvantages, procedure techniques, and follow-up of patients who undergo various endoscopic treatments for GERD. In addition, we will review the short and long-term success of these techniques in improving quality of life, use of PPI, and improvement in symptoms considering published data in high-quality peer-reviewed journals.

Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway.

Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G1-phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling.

Current controversies and advances in the management of pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is a lethal disease with a mortality rate that has not significantly improved over decades. This is likely due to several challenges unique to pancreatic cancer. Most patients with pancreatic cancer are diagnosed at a late stage of disease due to the lack of specific symptoms prompting an early investigation. A small subset of patients who are diagnosed at an early stage have a better chance at survival with curative surgical resection, but most patients still succumb to the disease in a few years. The dismal overall prognosis is due to suspected micro-metastasis at an early stage. Due to this reason, there is a recent interest in treating all patients with pancreatic cancers with systemic therapy upfront (including the ones that are surgically resectable). This approach is still not the standard of care due to the lack of robust prospective data available. Recent advancements in treatment regimens of chemotherapy, radiation and immunotherapy have improved the overall short-term survival but the long-term survival still remains poor. Novel approaches in diagnosis and treatment have shown promise in clinical studies but long-term clinical data is lacking. The following manuscript presents an overview of the epidemiology, diagnosis, staging, recent advances, novel approaches and controversies in the management of pancreatic adenocarcinoma.

New Era: Endoscopic treatment options in obesity-a paradigm shift.

The prevalence of obesity continues to rise, and along with it comes a multitude of health-related consequences. The healthcare community has consistently struggled with providing treatment options to obese patients, in part due to the reluctance of patients in pursuing the more effective (yet invasive) surgical approaches such as sleeve gastrectomy and Rou-en-Y gastric bypass. On the other hand, the less invasive approach such as lifestyle/behavioral interventions and pharmacotherapy (Orlistat, Phenteramine, Phentermine/Topiramate, Locaserin, Naltrexon/Buproprion, and Liraglutide) have very limited efficacy, especially in the morbidly obese patients. Despite our best efforts, the epidemic of obesity continues to rise and pose enormous costs on our healthcare system and society. Bariatric endoscopy is an evolving field generated to combat this epidemic through minimally invasive techniques. These procedures can be performed in an ambulatory setting, are potentially reversible, repeatable, and pose less complications than their invasive surgical counterparts. These modalities are designed to alter gut metabolism by means of space occupation, malabsorption, or restriction. In this review we will discuss different bariatric endoscopic options (such as intragastric balloons, endoscopic sleeve gastroplasty, endoscopic aspiration therapies and gastrointestinal bypass sleeves), their advantages and disadvantages, and suggest a new paradigm where providers may start incorporating this modality in their treatment approach for obese patients.

Serum Albumin at Diagnosis is an Independent Predictor of Early Mortality in Veteran Patients with Esophageal Cancer.

AIMS: To identify independent factors that could predict mortality within 6 months in a cohort of patients with esophageal cancer. METHODS: Esophageal cancer patients were grouped into early (≤6 months, n = 41) and late (>6 months, n = 81) mortality groups. 52 variables were analyzed by univariable analysis (UA). A multivariable (MVA) regression model was created to identify predictors of early mortality. RESULTS: When comparing early and late mortality groups, there was no difference in age, BMI, race, histology, or anatomic location between the two groups. UA demonstrated that the early mortality group had a lower mean albumin level (3.3 ± 0.1 g/dl vs. 3.8 ± 0.1 g/dl; P < 0.001), poorer ECOG performance status (1.9 ± 0.2 vs. 1.1 ± 0.1, P = 0.02), higher WBC count (9.6 ± 0.7 K/µL vs. 8.2 ± 0.3 K/µL, P = 0.04), and were less likely to receive surgery (2.4% vs. 22.2%; P = 0.003), neoadjuvant treatment (4.9% vs. 28.4%; P = 0.009) and definitive chemoradiation (7.3% vs. 27.2%; P = 0.01). MVA revealed that only low albumin at diagnosis was an independent predictor of survival (P = 0.016). CONCLUSION: Albumin level at diagnosis is an independent predictor of early mortality and might be used with other variables to provide prognostic information for patients and to guide treatment.

Epidemiology and Survival of Esophageal Cancer Patients in an American Cohort.

Objectives This study seeks to delineate trends in esophageal cancer patients in an American cohort and, in particular, examine the impact of race and histology on survival. Methods The association between over 50 variables between histology and race subgroups was evaluated. Survival was calculated using Kaplan-Meier curves and a multivariable Cox regression analysis (MVA) was performed. Results Poorer survival was noted in black vs. white (193 ± 65 days vs. 254 ± 39, 95% CI 205-295, p=0.07) and squamous cell cancer (SCC) vs. adenocarcinoma (AC) (233 ± 24 days vs. 303 ± 48, 95% CI 197-339, p=0.01) patients. In patients with resectable cancer, blacks had poorer survival than whites (253 ± 46 days vs. 538 ± 202, 95% CI 269-603, p=0.03), and SCC had poorer survival than AC (333 ± 58 vs. 638 ± 152 days, 95% CI 306-634, p=0.006). A higher percentage of white patients received surgery compared to black patients (36% vs. 8%, p=0.08). MVA revealed that only surgery was an independent predictor of mortality (p=0.001). Conclusion Black race and SCC were associated with poorer survival. On MVA, surgery was an independent predictor of mortality. Clinicians should be aggressive in offering potentially curative procedures to patients and eliminating socioeconomic barriers.

An unusual presentation of a benign pancreatic lesion containing amyloid.

We present a unique case of a benign pancreatic lesion which was positive for amyloid in a 55-year-old female patient without systemic amyloidosis. Further testing revealed islet-type amyloid polypeptide (or amylin), a protein found in various diseases such as diabetes, insulinoma and pancreatic adenocarcinoma-none of which was seen in our patient.

Lymphocyte-to-monocyte ratio can predict mortality in pancreatic adenocarcinoma.

AIM: To determine if the lymphocyte-to-monocyte ratio (LMR) could be helpful in predicting survival in patients with pancreatic adenocarcinoma. METHODS: We retrospectively reviewed the medical records of all patients diagnosed with pancreatic adenocarcinoma in the VA North Texas Healthcare System from January 2005 to December 2010. The LMR was calculated from peripheral blood cell counts obtained at the time of diagnosis of pancreatic cancer by dividing the absolute lymphocyte count by the absolute monocyte count. A Univariable Cox regression analysis was performed using these data, and hazard ratios (HR) and 95%CI were calculated. The median LMR (2.05) was used to dichotomize patients into high-LMR and low-LMR groups and the log rank test was used to compare survival between the two groups. RESULTS: We identified 97 patients with pancreatic adenocarcinoma (all men, 66% white, 30% African-American). The mean age and weight at diagnosis were 66.0 ± 0.9 (SEM) years and 80.4 ± 1.7 kg respectively. Mean absolute lymphocyte and monocyte values were 1.50 ± 0.07 K/µL and 0.74 ± 0.03 K/µL respectively. Mean, median and range of LMR was 2.36, 2.05 and 0.4-12 respectively. In the univariable Cox regression analysis, we found that an increased LMR was a significant indicator of improved overall survival in patients with pancreatic adenocarcinoma (HR = 0.83; 95%CI: 0.70-0.98; P = 0.027). Kaplan-Meier analysis revealed an overall median survival of 128 d (95%CI: 80-162 d). The median survival of patients in the high-LMR (> 2.05) group was significantly greater than the low-LMR group (≤ 2.05) (194 d vs 93 d; P = 0.03), validating a significant survival advantage in patients with a high LMR. CONCLUSION: The LMR at diagnosis is a significant predictor for survival and can provide useful prognostic information in the management of patients with pancreatic adenocarcinoma.

Survival analysis of veteran patients with pancreatic cancer.

OBJECTIVE: For patients with pancreatic cancer, the identification of reliable predictors of their outcomes could be invaluable for directing the managements. This study aimed to identify clinical and laboratory factors that could be used to predict early (≤6 months) or late (>6 months) mortality. METHODS: Medical records of patients diagnosed with pancreatic cancer in the VA North Texas Health Care System from 2005 to 2010 were retrospectively reviewed. Univariate and multivariate analyses (MVA) were performed and the utility of cancer antigen 19-9 (CA19-9) test was explored. RESULTS: Altogether 109 patients with pancreatic cancer, 89.0% of whom were with adenocarcinoma, were divided into early (n = 62) and late (n = 47) mortality groups. Kaplan-Meier analysis revealed a median survival of 154 days [95% confidence interval (CI) 93-194 days]. On MVA, abdominal pain (OR = 10.6, P = 0.009) and large tumor size (OR = 2.4, P = 0.028) were significantly associated with early mortality, while palliative chemotherapy (OR = 0.048, P = 0.001) and neuroendocrine tumor (OR = 0.009, P = 0.024) were significantly associated with late mortality. Subgroup analyses of adenocarcinoma and late-stage patients revealed similar results. Serum CA19-9 performed poorly as a prognostic indicator in both groups (P = 0.43), in metastatic disease at diagnosis (P = 0.32) and after treatment (P = 0.65). CONCLUSIONS: Abdominal pain and large tumor size portends a poor prognosis in patients with pancreatic cancer. Palliative chemotherapy and surgical intervention may prolong the patient's survival. CA19-9 is not universally reliable for predicting metastasis, survival, or the responses to chemotherapy.

Robotic cystogastrostomy and debridement of walled-off pancreatic necrosis.

Walled-off pancreatic necrosis is a known complication of acute pancreatitis and requires intervention if symptomatic or complicated. Laparoscopic cystogastrostomy as a minimally invasive surgical intervention has been well-described in surgical literature but data on a robotic approach is limited. Here we report a case of robotic cystogastrostomy and debridement of walled-off pancreatic necrosis in a patient with a history of severe biliary pancreatitis.

Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer.

Due to a wide range of clinical response in patients undergoing neo-adjuvant chemoradiation for rectal cancer it is essential to understand molecular factors that lead to the broad response observed in patients receiving the same form of treatment. Despite extensive research in this field, the exact mechanisms still remain elusive. Data raging from DNA-repair to specific molecules leading to cell survival as well as resistance to apoptosis have been investigated. Individually, or in combination, there is no single pathway that has become clinically applicable to date. In the following review, we describe the current status of various pathways that might lead to resistance to the therapeutic applications of ionizing radiation in rectal cancer.

The use of imaging and biomarkers in diagnosing Barrett's esophagus and predicting the risk of neoplastic progression.

Long-standing gastroesophageal reflux disease can result in transformation of the normal squamous lining of the esophagus into columnar epithelium (with goblet cells). This condition, Barrett's esophagus (BE), is considered a risk factor for esophageal cancer (EAC) and may be the cause of the increased incidence of EAC over the last few decades. Currently, endoscopy with biopsies revealing dysplasia is the best predictor for neoplastic progression in patients with BE. However, the use of more sophisticated imaging techniques and biomarkers with or without histological assessment may be helpful in more accurate prediction of malignant transformation in these patients. New approaches to the evaluation of BE such as epigenetics, miRNA analysis, detection of DNA content abnormalities and loss of heterozygosity have great potential to shed light on the complex gastroesophageal reflux disease -BE-EAC sequence.

Three-dimensional US volume analysis of gastric pseudotumors in a porcine model.

BACKGROUND: Tumor burden is difficult to estimate by endoscopy and conventional EUS. OBJECTIVE: The purpose of this study was to determine the accuracy and the reliability of a new 3-dimensional (3D) EUS system in a pseudotumor model (Olympus EUS EXERA EU-M60). DESIGN: A pseudotumor model was developed in a porcine stomach. Pseudotumors were created by injecting various volumes of US gel (0.3, 0.5, 0.7, and 1 mL) into porcine stomach specimens, and then the volume was measured in vitro. Two investigators made volume measurements by outlining the cross-sectional area of the pseudotumor at different radial planes. The instrument then automatically calculated the volume based on the outlined cross-sectional areas. The measured volume was compared with the actual volume of the pseudotumor by using a Bland-Altman analysis. Every second, third, fourth, fifth, sixth, and tenth image was measured to calculate the tumor volume and to determine the optimum number of images required for accurate volume determination. Inter- and intraobserver variability, percentage error, Bland-Altman analysis, analysis of variance (ANOVA), and kappa statistic were performed. SETTING: This study was performed in an in vitro animal model. PATIENTS: There were no patients involved in this study. MAIN OUTCOME MEASUREMENTS: Accuracy and reliability of pseudotumor volume measurement. RESULTS: When averaging across all measurements, the overall average mean error was 3.25%. The overall inter-rater reliability as measured by intraclass correlation coefficient was 0.78. The overall intra-rater reliability as measured by intraclass correlation coefficient was 0.99. Bland-Altman analysis and ANOVA showed similar low variability for measured volumes based on image frequencies for volume calculations between every other and every sixth image but greater variability for measured volumes based on every tenth image. Larger pseudotumors were measured with a slight decrease in mean percentage error. The kappa statistic for interobserver variability was .61, which demonstrated substantial agreement among observers. LIMITATIONS: The major limitation of this technology is the penetration of the US beam to evaluate large tumors, because the US transducer is high frequency (20 MHz) and, therefore, has a limited penetration. CONCLUSIONS: In conclusion, the new Olympus EUS EXERA EU-M60 3D US probe allowed for accurate volume measurements of small pseudotumors in porcine stomach model in vitro. There was substantial evaluator agreement, with a low interobserver variability. Larger pseudotumors were measured with a slightly lower percentage error than smaller pseudotumors. Volumes measured with a greater number of radial images were measured slightly more accurately. We plan to test this device in patients with GI tumors in the near future.

Use of endoluminal ultrasound to evaluate gastrointestinal motility.

The use of high-frequency ultrasound transducers in the gastrointestinal tract (GI) has already yielded remarkable findings concerning the anatomy, physiology and pathophysiology of the GI tract and of various motility disorders. These transducers have made completely invisible portions of the GI tract (the longitudinal smooth muscle, muscles of the upper esophageal sphincter, components of the gastroesophageal junction high-pressure zone, and the muscle of the anal sphincter complex) accessible to investigation. Use of simultaneous ultrasound and manometry has allowed the exploration of the normal physiology of peristaltic contraction. The components of the high-pressure zone of the distal and proximal esophagus have been isolated and the movement of these components has been studied individually and as a group. Various esophageal motility disorders have been investigated including achalasia, scleroderma, Barrett's esophagus and diffuse esophageal spasm. The possible etiology of the symptoms of esophageal chest pain and heartburn (sustained esophageal contractions of the longitudinal smooth muscle), have been studied. The possible underlying pathophysiology of GERD (the missing gastric clasp and sling fiber pressure profile) has been explored. Three-dimensional high-frequency ultrasound imaging has allowed the peristaltic contraction sequence to be viewed in a completely new and unique manner. The biomechanics of both esophageal contraction and the gastroesophageal junction high-pressure zone have been investigated and the mechanical advantage of esophageal shorting has been studied. The mechanism of action of standard surgical and newer endoscopic therapies for GERD has been defined. Future applications of this technology are limited only by our imagination.